Analysis of ion currents contribution to repolarization in human heart failure using computer models

The mechanisms underlying repolarization of the ventricular action potential (AP) is subject of research for anti-arrhythmic drugs. In fact, the prolongation of the AP occurs in several conditions of heart disease, such as hypertrophy and heart failure, when changes in ion channels activity take place. An important feature of the repolarization process is the all-or-none behavior, which depends on the delicate balance of inward and outward currents in the different phases of the AP. Another important concept in AP repolarization is “repolarization reserve” defined as the capacity of the cell to repolarize in case of a functional loss. In this study we investigated the phenomena of repolarization reserve and the all-or-none repolarization under conditions of human heart failure (HF), a major problem precursor for serious arrhythmias. To simulate HF conditions, the O'Hara et al. And Grandi et al. human AP models were modified and specific protocols for all-or-none repolarization were applied. Our results show that in the early repolarization the threshold for all-or-none repolarization is not altered in HF even if a decrease in potassium currents can be observed. To quantify the contribution of the individual ion currents to HF induced AP prolongation, we used a novel piecewise-linear approximation approach proposed by Paci et al. Our results highlight this novel algorithm as a powerful tool to have a more complete picture of the complex ionic mechanisms underlying this disease and confirm the important role of the late sodium current in HF repolarization.